Hi, it's Dr. David Rubin from the University of Chicago. I'm at the American College of Gastroenterology Annual Meeting in Philadelphia and it's 2024, and they have had an amazing attendance here, record breaking in-person attendance of over 6500 people at the postgraduate course, and what I'm told was almost 8000 people at the overall meeting. I had the pleasure of speaking about managing ulcerative colitis and specifically positioning our therapies to manage people who live with this condition. And I spoke during the postgraduate meeting. I emphasized a number of lessons about taking care of people with ulcerative colitis, starting with recognizing how much has changed since the practice guidelines we published in 2019. There have been over 9 new therapies that have been approved by the FDA in the United States and a variety of other strategies to managing people with ulcerative colitis that was important for our colleagues to learn.

The first thing I emphasized was to understand the basic principle of our goal for managing ulcerative colitis. In fact, what I said to the audience is it's the destination, not the journey. In other words, what I meant was if we expect to get patients into stable functional remission, meaning that they're feeling great and their bowel is healed or the disease process is otherwise controlled, they're likely to do well. And that goal should drive our decision making. Regardless of which treatment you necessarily start with, you want to make sure you're moving along until you get there. I also emphasize the importance of raising expectations of our patients so they know to expect that goal. We want people to live with an unencumbered quality of life, and of course we want it to be a high quality of life. So to get there, we have to understand some basic principles about how we take care of ulcerative colitis.

That includes understanding how to grade the activity of the disease. And our field has in fact moved to accept that the mucosal inflammation of the bowel is a marker of not just how active the disease is, but it's a prognostic indicator of what might happen if it's undertreated or untreated over time. I also emphasized that we're now recognizing the role of calprotectin as a measure of inflammation, a measure of response to therapy, and actually as a predictor of outcomes as well. And the emerging appreciation for the value of bedside point of care intestinal ultrasound as a way to measure bowel wall thickness and hyperemia, blood flow in that bowel, to understand how inflamed people are. So recognizing that you need to understand the extent of the colitis, the activity of that severity, and then understand the consequences of untreated disease by talking about prognosis is the way to know how you might then start treating people.

When it comes to prognosis, we've made some additional progress there as well. As much as we already know that the patient with more extensive disease and more severe disease on endoscopy has a higher risk for hospitalization and surgery, we have also come to realize that there are other predictors of that bad outcome as well. One of them is the coexistent extraintestinal manifestations, which raises the likelihood that the patient's going to have more problems and might lead to hospitalization or a need for additional therapies. We also recognize that the patient who has mood or mental health disorders has a higher risk for poor outcomes for a variety of different reasons that you might understand. And we emphasize the importance of screening and providing appropriate resources to treat those individuals. And we now start to acknowledge more and more the value of appreciating the socioeconomic status and specifically those who are uninsured or underinsured and who have a variety of different social determinants that will predict poor outcomes.

And in part on our side that we haven't been educated or using our newer therapies properly. So recognizing that the conventional therapies for managing colitis are limited in many different ways, we should be identifying people who are not adequately treated and moving them along to the other treatments. To this point, I want to emphasize another important issue, which is that if we don't look and we don't talk about it, we don't know to move people along and that sets them up for worse outcomes, including a worse quality of life, which we don't want for our patients. So moving along, then we have to acknowledge and we should be appreciating that we have many new therapies that have been shown to be effective for treating moderately to severely active and moderate to severe, meaning the prognosis, ulcerative colitis. And those treatments need to be used appropriately.

Regardless of what therapy you're most comfortable starting with, you should acknowledge that the patient with moderately to severely active UC, even the patient who needs one course of steroids as an induction strategy, is somebody that needs to be treated with a therapy that's approved for moderately to severely active UC. That may sound very obvious, but I think we're not doing it enough. So the first point to understand is that most of our new therapies have an induction phase and a maintenance phase. And I summarized that one of the strategies that's evolved in ulcerative colitis and for Crohn's disease has been the recognition that in bowel inflammation, distinct from dermatology and rheumatology, we use higher doses of therapy to induce and different doses often now in maintenance. In fact, there is the IV loading phase of our induction therapies followed by maintenance dosing with many of our treatments.

In the TNF therapies, we now have subcutaneous infliximab, a biosimilar to the originator that you can use in maintenance, but it starts with the IV loading that we've all used over many years. Similarly, we also now in the US have subcutaneous vedolizumab, the anti-integrin therapy, after 2 doses of IV loading. So the IV phase to get people under control and get the drug into their system and the maintenance phase, which can be subcutaneous. I even emphasized that the sub-q frequent dosing of sub-q infliximab and sub-q vedolizumab actually may have a favorable pharmacokinetic profile. It actually results in a more stable serum level of drug over time, which actually can contribute to more stable control, and we believe less loss of response. And in the infliximab patients, we think it may also lead to less immunogenicity or neutralizing antidrug antibodies. So there's some benefits to understanding this from the standpoint of favorable pharmacokinetics and maybe a new way to look at our old friend, infliximab and our old friend vedolizumab.

In the IL-23 class, we now have three additional p19 inhibitor drugs that are available for ulcerative colitis. They include guselkumab, mirikizumab, and risankizumab. All three of these drugs target a protein called P19, and P19 is a protein that is unique to the Interleukin-23 antibody. And we know that this pathway is effective in managing patients with moderate to severe ulcerative colitis. All 3 of those drugs have IV loading phases and subcutaneous maintenance phases. And we should acknowledge as well that there are some variable dosing options for the use in maintenance that we're learning more about, but which work very nicely. And again, emphasize the important point that IV induction and having successful induction of remission and response leads to less intense strategies for maintenance with the subcutaneous dosing and what we think is a very effective strategy for long-term control. The nice thing about IL-23 inhibitors is that they have an established and very nice safety profile across all of these therapies that we see now and we understand is very important for our patients, and we certainly want to understand ourselves.

One of the messages I shared is that in order to distinguish between using an IL-23 inhibitor, the anti-integrin therapy, vedolizumab, or an anti-TNF inhibitor like infliximab or adalimumab, you also need to understand a bit more about the possibility or the existence of comorbid immune conditions or extraintestinal manifestations, the most common of which is joint pain, whether it's a peripheral or axial spondyloarthropathy, in which case we would favor an anti-TNF and ultimately the possibility of a Janus kinase inhibitor. Or we can think about the patient who might have skin manifestations of their disease or coexistent plaque psoriasis or psoriatic arthritis, in which case we might favor the use of an IL-23 inhibitor. So there are some strategies we can think about to choose therapies.

The other important message that I shared was what I think is a revolution in managing our patients with IBD, which is the availability of our novel targeted small molecules. We now have 2 classes available in ulcerative colitis and specifically for moderately to severely active ulcerative colitis. The first class are the S1P receptor modulators. These are therapies that actually bind to the receptor related to the detection of signaling molecules and prevent egress of activated lymphocytes from the lymph nodes and essentially shut down lymphatic trafficking of the activated white blood cells that are going to drive the colitis. There are 2 drugs available, ozanimod and etrasimod, and both of these therapies have been shown to be effective in moderate to severe UC, but also they are oral, once a day therapies that have a very nice safety profile. And the class of therapy, and specifically as well, ozanimod, has been used in multiple sclerosis for years. And we know from their safety experience as well that these are very well tolerated and acceptable therapies that we can use in our patients.

The other oral therapy and targeted synthetic small molecule are the Janus kinase inhibitors, which I've already mentioned. In the United States, they have to be positioned after the use of an anti-TNF therapy. So it's important to understand how you might be thinking ahead to using one of these therapies. In other parts of the world, that's actually not required, but in the US, that's how the label is listed. And we have two of those drugs that are available, tofacitinib and upadacitinib. In Europe, they also have filgotinib. Now the distinction between these drugs is based on the selectivity to specific Janus kinase enzymes. Tofacitinib is what we call a pan-JAK inhibitor. It seems to be affecting JAK1, JAK2, and JAK3, maybe even a little bit of TYK2, which is the fourth Janus kinase inhibitor or Janus kinase enzyme. And upadacitinib and filgotinib are both JAK1 selective inhibitors.

These are also oral therapies that work quite fast and work on multiple inflammatory pathways by inhibiting signal transduction and activation at the level of those enzymes. So there are ways to think about those therapies in specific patients. The JAK inhibitors are also approved by the FDA for the treatment of the spondyloarthropathies and rheumatoid arthritis. And you can think about the patient who may have joint problems and how you might select therapies in that scenario. And specifically with the JAKs, you have to go through an anti-TNF before you get to them. So you have to be thinking ahead about where you're going and when you might need that specific treatment.

The other lesson that I emphasized to the audience was that as you think about using these different therapies, as you appreciate the induction and maintenance phases of these therapies, you should also think about how do you assess how somebody is doing.  Usually we of course want patients to feel better as quickly as possible. For some of our therapies, that's in days now, not weeks or months, but we certainly want them to have some objective measure of improvement by an early point in time. In my own practice, that's at about 6 weeks where I will reassess with either a CRP if the patient has an elevated CRP at baseline or a repeat calprotectin as a sensitive marker of inflammation of the bowel to give me a guide that that patient in fact is controlling their inflammation. And remember, some patients will describe improvement in symptoms, but will still have active inflammation and you want to make sure you're moving along to get both under control.

Now having said that, one of the other lessons in my lecture was about adopting an operationalized treat to target strategy. What do I mean by that? It means thinking ahead to what marker are you going to use for an individual patient, talking to the patient about how you're going to monitor their response to therapy and adjust their therapy as necessary. And also working with your team, your nurses, your pharmacists, your medical assistants, and your advanced practice providers to think about how you do this for every patient. In my own practice, my wonderful team works with me. And when we put a patient on a new therapy, we will preschedule them for follow up at 2 weeks by phone or by televisit, and a follow-up at 6 weeks to repeat an objective measure like a calpro or CRP. I also always tell patients they should not be getting worse while we're trying to treat them for their condition.

I moved along in my presentation to talk about how do you assess somebody who's not at target and how do you assess somebody who may be losing response to therapy? And in that specific scenario, I discussed a bit more, making sure the patient is not infected, making sure they're truly inflamed when they have persistent symptoms, and then assessing what's happening with the drug. Was the patient able to start it as prescribed? Are they taking it as prescribed? In the case of anti-TNF, which is the only one where we should be doing this, are they developing antidrug antibodies or is there rapid clearance of that based on what we've learned? And if we need to, can we dose escalate? Can we add a second therapy? Or should we switch classes altogether?

To that point, I updated the audience on some newer data that's emerging, both real-world data, as well as some of the analyses from our clinical trials that suggest that it might be better, especially now, to switch classes entirely rather than to try to cycle and stay within a class when it's not working.

Now, there are some data to suggest that within-class cycling has some benefit. For example, we started to learn that patients not doing well with ustekinumab, the old IL-12/ IL-23 inhibitor, which is still an effective and available drug, might do well if we switch them to a p19 inhibitor. We have the data specifically now with risankizumab, and it's presumed that this is likely to be true as we switch to the other P19 inhibitors, although those data are forthcoming and ongoing studies will help us understand that.

The other thing to keep in mind is that repeatedly in the real world and in our experience now, we've come to appreciate that adalimumab is not a very effective anti-TNF in many patients with ulcerative colitis. Infliximab seems to be the preferred therapy, whether it's the usual IV induction and IV maintenance or the new subcutaneous maintenance, infliximab is the preferred anti-TNF therapy. So if you're using adalimumab and they're not responding, there may still be a role for infliximab, but if you're using infliximab and they're not responding, going to another anti-TNF, whether it's adalimumab or golimumab, is not really appropriate and you should be moving on to another class of therapy. It can be your anti-integrin even. It can be your IL-23, and it certainly can be one of your small molecule strategies to think carefully about.

Now, I ended my presentation by giving the audience some pearls about optimizing access, which in the United States is a real challenge. And that includes making sure your documentation is appropriate. So you're explaining this to the patient with the degree of disease you describe, and that you educate your patient to make sure they're answering calls from the insurance company, which may come from a phone number they don't recognize, and that you also know your resources and expect that you may have to appeal at least once for most preauthorizations.

Again, operationalizing this with your staff can make things much easier. I provided a reference and a resource which is easily found online for the insurance commissioner, which exists in every state in the United States, who can review a situation if you've been denied and you feel that it's inappropriate from an insurance payer. I concluded with an algorithm that suggests making sure you're treating patients and getting them to the ultimate goal of sustained functional remission. Treat the mild to moderate patients as we've learned over the years with 5-ASA, maybe a single course of steroids, and the possibility in some situations thiopurines, but moving along early to those patients with persistent moderate or those patients who need steroids to your advanced therapies, and certainly those with moderate to severe disease, both activity and that prognosis, you should be using the appropriate therapies and guaranteeing that your patients are getting close to their targets and that you're monitoring them appropriately.

Thinking ahead and looking for extraintestinal manifestations and coexistent immune conditions can guide you in additional treatment choice. I appreciated the opportunity to present to our colleagues, and I certainly appreciate the opportunity to summarize it for you, and I hope that you found this helpful.